ABSTRACT ? PROJECT 1 Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and an important cause of morbidity and mortality from hematopoietic malignancies in adults. ALL is a paradigm for chemotherapy-responsive human cancers. Due to decades of large scale clinical trials, and the ability to obtain tumor material prior to and during therapy, childhood ALL treatment has helped to establish the importance of characterizing somatic genetic alterations and measurement of early treatment response (minimal residual disease, MRD) as the two strongest predictors of ALL outcomes. Importantly, many drugs used to treat ALL, e.g. glucocorticoids, methotrexate, and thiopurines, are used for a range of malignant and non-malignant conditions, and are associated with short and long-term toxicities that limit escalation of dose intensity to improve treatment outcomes. New treatment approaches based on rational targets and tailored to individual patients, are required to further improve treatment outcomes in ALL. In the last decade, genome wide profiling has transformed understanding of the genetic basis of ALL, identified new ALL subtypes, defined the inherited and somatic genetic alterations that define each subtype, and importantly, highlighted specific genomic alterations that may be used for initial diagnosis, refinement of risk stratification, and the development of targeted therapeutic approaches. However, the majority of these data have been derived from childhood ALL cohorts, and the genetic basis of ALL in adults, which has an inferior outcome, is poorly understood. The goal of this project is to perform a large-scale, integrated genomic, transcriptomic and epigenomic analysis of childhood and adult ALL, to comprehensively define the genomic landscape of ALL and identify features associated with treatment response (MRD) and outcome. Aim 1 will define the landscape of somatic genetic alterations of over 1900 cases of childhood and adult ALL, drawn from clinical trials that include ascertainment of clinical features, to identify associations of individual features with MRD and outcome. These studies will identify sequence alterations using exome and transcriptome sequencing, gene rearrangements, gene expression and mutation expression by RNA-sequencing, structural genetic alterations by single nucleotide polymorphism (SNP) arrays, and cytosine methylation profiling using methylation arrays (Cores B and C). Aim 2 uses SNP microarrays of germline (non-tumor) samples of over 900 adult and 6600 childhood ALL cases, with 1900 patients overlapping with Aim 1, to perform genome wide association studies (GWAS) to identify inherited variants associated with MRD and with outcome in children and adults. In Aim 3, we will perform an integrated analysis of inherited and somatic genetic features with outcome and MRD, incorporating the univariable analyses of specific genetic alterations identified in Aims 1 and 2 to test agnostic cross-platform genome-wide approaches to identify predictors of outcome. These integrated ?omic predictors will be combined with those identified in Projects 2 and 3 to build a comprehensive model of precision medicine approaches in Core C.